Sprouty (Spry) is a family of intracellular proteins that are endogenous regulators of receptor tyrosine kinase pathways such as the Ras/MAP kinase pathway. Sprouty was first identified in Drosophila as an inhibitor of fibroblast growth factor (FGF)-induced tracheal branching (Hacohen et al. (1998) Cell 92:253-263) and epidermal growth factor (EGF)-induced eye development (Casci et al. (1999) Cell 96:655-665). Mammalian species express four isoforms of Sprouty (Spry1-4) (Hacohen et al. (1998) Cell 92:253-263; de Maximy et al. (1999) Mech. Dev. 81:213-216; Minowada et al. (1999) Develop. 126:4465-4475), which act as inhibitors of growth factor-induced cellular differentiation, migration, and proliferation (Gross et al. (2001) J. Biol. Chem. 276:46460-46468; Impagnatiello et al. (2001) J. Cell Biol. 152(5):187-1098; Yigzaw et al. (2001) J. Biol. Chem. 276:22742-22747; Hanafusa et al. (2002) Nat. Cell Biol. 4:850-858). Although this antagonistic function is mediated by the ability of Sprouty proteins to regulate the RTK-RAS/mitogen-activated protein kinase (MAPK) pathway, the protein(s) on which they exert their action appears to be highly signal-specific (Gross et al. (2001) J. Biol. Chem. 276:46460-46468; Hanafusa et al. (2002) Nat. Cell Biol. 4:850-858; Sasaki et al. (2003) Nat. Cell Biol. 2:281-282).
At least four Sprouty proteins have been identified in humans. The specific role of Sprouty2 in the regulation of RTK signaling in human cells appears more complicated than in other mammalian cells. Recent evidence shows that in addition to the antagonistic function, Sprouty2 also acts as an agonist of the RTK pathway, specifically the epidermal growth factor receptor (EGFR) pathway (Egan et al. (2002) Proc. Natl. Acad. Sci. U.S.A. 99:6041-6046; Wong et al. (2002) EMBO J. 21:4796-4808; Rubin et al. (2003) Curr. Biol., 13:297-307). This agonistic function is the result of the interaction of Sprouty2 with c-Cbl, an E3 ubiquitin ligase that catalyzes the ubiquitination of EGFR, targeting this receptor for proteosomal degradation (Thien et al. (2001) Nat. Rev. Mol. Cell. Biol. 2:294-307). By binding to c-Cbl, Sprouty2 prevents the interaction between c-Cbl and EGFR, and this blocks the degradation of the receptor, which leads to sustained EGFR-induced ERK activity (Wong et al. (2001) J. Biol. Chem. 276:5866-5875; Egan et al. (2002) Proc. Natl. Acad. Sci. U.S.A., 99:6041-6046; Wong et al. (2002) EMBO J. 21:4796-4808; Rubin et al. (2003) Curr. Biol. 13:297-307). While the antagonistic function of Sprouty2 regulates several cellular functions, little is know about the cellular functions that are regulated by the agonistic function of Sprouty2.